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Editor—Warwick and Corrall report on a patient whose international normalised ratio changed while she was receiving multiple drugs, including oral terbinafine and warfarin.1 The authors suggest that this was because of an interaction between warfarin and terbinafine, but the case is more complex than it seems. The patient was taking four other drugs besides terbinafine (glibenclamide, metformin, frusemide, and spironolactone), which may have been interacting with warfarin after its biotransformation by a number of cytochrome P-450 enzymes. In addition, warfarin may interact with many other compounds, including beverages, food supplements, food stuffs, and food additives.2
Both terbinafine and warfarin are metabolised by cytochrome P-450 2C9 subclass. Terbinafine, however, has a low potential to induce cytochrome P-450, as it does not affect the disposition or the metabolism of antipyrine.3 Also, a pharmacokinetic study of a single dose of warfarin in healthy volunteers treated with terbinafine showed no significant interaction.4 Additionally, in a postmarketing surveillance study of the use of terbinafine in over 10 000 patients, a total of 26 patients received concomitant warfarin. No adverse events associated with coagulation were reported.5
Since oral terbinafine was launched in 1991 over seven million patients are estimated to have received it. The adverse events reported to Novartis Pharma AG include single cases in which both prolongation of as well as a reduction in the prothrombin time has been described. Single reports describing inconsistent patterns exist with other oral anticoagulant treatments.
On review of the reported case, and in the light of all other available evidence, we believe that one cannot make a generalisation regarding an interaction between terbinafine and warfarin. In those rare cases in which terbinafine and warfarin are combined with other drugs, routine follow up (as is general medical practice in patients taking warfarin) should ensure adequate detection. Since its launch, oral terbinafine has shown an excellent safety profile.
2.Stockley IH. Drug interactions. 4th ed. London: Pharmaceutical Press; 1996. pp. 994–995. [Google Scholar]
3.Seyffer R, Eichelbaum M, Jensen JC, Klotz U. Antipyrine metabolism is not affected by terbinafine, a new antifungal agent. Eur J Clin Pharmacol. 1989;37:231–233. doi: 10.1007/BF00679775. [DOI] [PubMed] [Google Scholar]
4.Guerret M, Francheteau P, Hubert M. Evaluation of effects of terbinafine on single oral dose phamacokinetics and anticoagulant actions of warfarin in healthy volunteers. Pharmacother. 1997;17:767–773. [PubMed] [Google Scholar]
5.O’Sullivan DP, Needham CA, Bangs A, Atkin K, Kendall FD. Postmarketing surveillance or oral terbinafine in the UK. Br J Clin Pharmacol. 1996;42:559–565. doi: 10.1111/j.1365-2125.1996.tb00110.x. [DOI] [PubMed] [Google Scholar]
Editor—Gantmacher et al from Novartis suggest that other drugs taken by our patient may have contributed to the observed interaction between oral terbinafine and warfarin leading to a fall in her international normalised ratio. Not only were all her other drug treatment stable for 24 months before the course of terbinafine, however, but none of these medicines (glibenclamide, metformin, frusemide, and spironolactone) are listed by the British National Formulary as having the potential to interact with warfarin. Our patient had no major changes in diet or alcohol consumption during this time. Furthermore, studies of single doses of warfarin in healthy volunteers treated with terbinafine may satisfy the requirements of the regulatory licensing authorities but are inadequate to detect the relatively gradual process of induction of liver enzymes.
We still believe that our observations merited a report. We would also be interested to know whether Novartis has received any other reports of interactions with warfarin from any of the voluntary schemes for reporting adverse drug reactions.
BMJ. 1998 Jul 18;317(7152):205.
Systematic review of interaction profile of warfarin is needed
Editor—Warwick and Corrall’s description of a possible interaction between warfarin and terbinafine2-1 was an unwelcome addition to the jumble of anecdotal data surrounding warfarin, an old drug known to interact with numerous prescription only medicines, over the counter remedies, and foodstuffs. As Dollery et al have pointed out, warfarin has a narrow therapeutic index and thus suspicions of interactions are easily occasioned by random fluctuations in the international normalised ratio.2-2
The number of drugs listed in the September 1997 issue of the British National Formulary as having important interactions with warfarin is large (74 drugs from 23 classes are named explicitly), and Stockley lists 275 reported interactions, including at least 12 involving over the counter preparations and over 20 involving beverages, foodstuffs, food supplements, and food additives.2-3
Reliable published data show that warfarin does not have a kinetic interaction with terbinafine.2-4 Furthermore, a postmarketing surveillance study of terbinafine carried out in Britain and Northern Ireland did not find any cases of warfarin interacting with terbinafine even though 26 patients were taking both drugs.2-5 Clearly there is little cause for concern.
Anecdotal case reports of drug interactions involving warfarin do little to inform prescribers. What is needed is an up to date systematic review of the interaction profile of the drug. The need for this has become more urgent now that warfarin is being used much more frequently in the management of an ever growing range of circulatory disorders.
2-3.Stockley IH. Drug interactions. 4th ed. London: Pharmaceutical Press; 1996. pp. 994–995. [Google Scholar]
2-4.Gueret M, Francheteau P, Hubert M. Evaluation of effects of terbinafine on single oral dose kinetics and anticoagulant actions of warfarin in healthy volunteers. Pharmacother. 1997;17:767–773. [PubMed] [Google Scholar]
2-5.O’Sullivan DP, Needham CA, Bangs A, Atkin K, Kendall FD. Postmarketing surveillance of oral terbinafine in the UK: report of a large cohort study. Br J Clin Pharmacol. 1996;42:559–565. doi: 10.1111/j.1365-2125.1996.tb00110.x. [DOI] [PubMed] [Google Scholar]
